Biomedical subjects

J Kadota

Publications and source records attributed to J Kadota.

At least 109 records · Page 6Linked to original sources

PubMed1992

[Tumor associated carbohydrate antigens in bronchoalveolar lavage fluid in patients with diffuse panbronchiolitis].

It is known that tumor associated carbohydrate antigens are significantly increased in the serum of patients with diffuse panbronchiolitis (DPB). We investigated carbohydrate antigens (SLX, CA19-9) in bronchoalveolar lavage fluid (BALF) obtained from 24 patients with DPB. The concentrations of SLX and CA19-9 were significantly higher in BALF from patients with DPB than those from healthy subjects (7 cases) and patients with pulmonary sarcoidosis (16 cases). No significant correlation was observed between either SLX or CA19-9 concentrations in the serum and BALF, and no significant correlation was observed between the concentrations of these carbohydrate antigens in BALF and clinical findings. Immunohistochemical study of SLX and CA19-9 in open lung biopsy specimens obtained from patients with DPB showed expression of SLX and CA19-9 on the bronchiolar surface epithelial cells and mucinous exudates in air spances. These results indicate that carbohydrate antigens are presumably increased in the pulmonary lesions of patients with DPB, and this increase causes high levels of these antigens in the serum. Furthermore, we investigated the change of concentrations of SLX and CA19-9 in BALF obtained from patients with DPB after erythromycin (EM) treatment. The concentrations of these two antigens were decreased after EM treatment.

Adolescent↗

PubMed1992

[A clinical study of the long-term therapeutic effects of low-dose erythromycin in diffuse panbronchiolitis--with special reference to changes in tumor-associated carbohydrate antigens in serum].

We investigated the long-term (3-30 months) therapeutic effects of low-dose (300-600 mg/day) erythromycin in 26 patients with diffuse panbronchiolitis (DPB). Significant improvements of pulmonary functions especially in %VC and PaO2 as well as respiratory symptoms were shown. However, erythromycin treatment was not associated with a significant change in surface phenotypes on peripheral blood lymphocytes (CD4, CD8, CD4/CD8). It is well known that serum levels of tumor-associated carbohydrate antigens such as SLX (sialylated Lewis X-i) and CA19-9 (sialylated Lewis(a)) are significantly elevated in patients with DPB. In the present study, 68.4% (13/19) of DPB patients showed marked elevation of SLX and 52.9% (9/17) showed marked elevation of CA19-9 levels in serum. These positive ratios were significantly decreased by erythromycin treatment to 31.6% (6/19) in SLX and 23.4% (4/17) in CA19-9. The mean values of each marker were also significantly decreased after erythromycin administration from 54.9 +/- 26.9 U/ml to 39.5 +/- 22.1 U/ml for SLX and from 70.5 +/- 77.4 U/ml to 28.8 +/- 37.4 U/ml for CA19-9.

Adolescent↗

PubMed1992

[A case of sarcoidosis with hypercalcemia, urolithiasis, nephrocalcinosis and renal insufficiency].

A sixty nine-year-old woman was admitted to the hospital because of further examination of hypercalcemia. On July 1990, she complained of general fatigue and loss of appetite. She was pointed out to have hypercalcemia (15.1mg/dl), urolithiasis, and renal insufficiency. CT films of the chest showed swelling of the mediastinal lymphnodes and CT of the abdomen nephrocalcinosis. Ga-scintigraphy demonstrated an abnormal accumulation of gallium in the mediastinum. Levels of the parathyroid hormone was normal. Levels of the serum calcium (13.7mg/dl), angiotensin converting enzyme (30.4IU/L) and 1.25 (OH)2D (87PG/ml) were elevated. Giant cells were found in the biopsy specimen of the lung. A significant relationship between the serum calcium and creatinine were observed (r = 0.76, p < 0.02). Proximal fractional reabsorption of sodium showed to be suppressed (47.7%), and distal fractional reabsorption of sodium showed to be normal (88.4%). From these findings hypercalcemia and urolithiasis was suggested to result from sarcoidosis. The hypercalcemia and renal insufficiency improved with corticosteroid therapy.

Aged↗

PubMed1992

[Epidemiology of HTLV-I carriers in Hirado Island and virological and immunological investigation of HTLV-I associated pulmonary disease].

Adult T-cell leukemia (ATL) is endemic in Kyushu. Our study at Hirado island in Nagasaki prefecture revealed a higher incidence (35.9%) of HTLV-I carriers in villages with fishing than in those without (16.5%). HTLV-I carriers showed a higher incidence of abnormal findings on chest roentgenogram (21.7%) than non-carriers (16.5%), but most were lesions of old pulmonary tuberculosis and pleural thickening. Virological and immunological investigations were performed for 10 HTLV-I carriers, 3 patients with HTLV-I associated myelopathy (HAM), and 3 patients with ATL to determine the presence of HTLV-I associated pulmonary disease. In HAM patients, there were high titers of anti HTLV-I antibody, positive IgA reaction to HTLV-I, and an increase in interleukin-2 receptor (IL-2)-positive T-cells in the peripheral blood; and lymphocytosis and an increase in IL-2-positive T-cells in the bronchoalveolar lavage fluid (BALF). Virological examination showed the presence of pX gene and tax1/rex1 mRNA in the peripheral blood and BALF. Similar immunological and virological findings in 2 of 10 carriers suggested the presence of HTLV-I associated pulmonary disease.

Aged↗

PubMed1991

A synthetic peptide homologous to retroviral transmembrane envelope proteins depresses protein kinase C mediated lymphocyte proliferation and directly inactivated protein kinase C: a potential mechanism for immunosuppression.

CKS-17, an immunosuppressive peptide homologous to certain retroviral transmembrane envelope protein, has been shown to inhibit lymphocyte proliferation in response to mitogens or alloantigens when covalently attached to bovine serum albumin (CKS-17-BSA). To define its site of action, we determined if CKS-17 conjugated to human serum albumin (CKS-17-HSA) could block the direct activation of lymphocytes by phorbol-12-myristate-13-acetate (PMA) or by a synthetic diacylglycerol, dioctanoylglycerol (DiC8). CKS-17-HSA inhibited lymphocyte proliferation in response to PMA and ionomycin in a dose-dependent manner with up to 88% inhibition occurring with 15 microM CKS-17-HSA. The conjugated peptide also inhibited the proliferation of lymphocytes in response to DiC8 and ionomycin by up to 57% at 15 microM CKS-17-HSA. Based on these findings we investigated the effect of CKS-17-HSA on the activity of protein kinase C (PKC), an enzyme directly activated by PMA and DiC8. PKC was isolated chromatographically from the cytosol of human neutrophils or the human lymphoblastoid cell line Jurkat. CKS-17-HSA caused a dose-dependent enzyme inhibition with a concentration giving half-maximal inhibition (IC50) of ca.3 microM and greater than 95% inhibition at 15 microM CKS-17-HSA. Inhibition of PKC by the conjugated peptide was not reversed by increasing concentrations of Ca2+, Mg2+, phosphatidylserine, diolein, or adenosine triphosphate (ATP), indicating that the conjugated peptide did not function as a chelator or competitive inhibitor. In contrast to its effects on PKC, CKS-17-HSA did not inhibit the activity of adenosine 3':5'-cyclic monophosphate (cyclic AMP)-dependent protein kinase (PK-A) nor the calcium and phospholipid-independent form of PKC (PK-M). Moreover the peptide inhibited in vivo PKC activity in cytosol of intact cells and in membrane of PMA-stimulated cells. These results suggest that the inhibition of lymphocyte proliferation by CKS-17-HSA may be due to the direct inactivation of PKC.

Amino Acid Sequence↗

PubMed1991

[Effect of erythromycin on neutrophil function in chronic respiratory tract diseases with Pseudomonas infection].

The "low dose and long term" erythromycin (EM) therapy has been reported as effective (or useful) in chronic respiratory tract disease with pseudomonas (P.) infection including diffuse panbronchiolitis (DPB), however the mode of action is still obscure. Therefore in this study we have examined the effect of EM on the interaction between P. aeruginosa and human polymorphonuclear leukocyte (PMN) in vitro. The efficiency of intracellular killing and the ability of superoxide production were employed to evaluate the PMN functions. For the first step, the following results were obtained; 1) Pretreatment of PMN with 20 micrograms/ml EM did not affect the killing ability of PMNs against opsonized P. aeruginosa of standard and clinical isolate from DPB patient. 2) Superoxide production from PMNs was observed by phagocytosis of P. aeruginosa in the presence of serum. This was not affected by exposure of PMNs to 20 micrograms/ml EM even with increased ratios of bacteria to cells. 3) Pretreatment of P. aeruginosa with 20 micrograms/ml EM before opsonization enhanced the killing ability of PMNs in both standard and clinical isolate. 4) Pretreatment of P. aeruginosa with 20 micrograms/ml EM resulted in no effect on superoxide production from PMNs by phagocytosis of the bacteria. These results indicate that EM may modify a certain step of the interaction between bacteria and intracellular host defence mechanisms. Therefore for the second step, we have investigated the susceptibility of EM-exposed bacteria to killing by the cell free (glucose oxidase-glucose) system, which will detect the enzymatic generation of hydrogen peroxide (H2O2). The following results were observed; 1) EM-exposed bacteria was more susceptible to killing than control bacteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchiolitis↗

PubMed1991

[A study of bronchoalveolar lavage analysis in patients with diffuse panbronchiolitis--the results of low dose and long term erythromycin treatment].

Cellular analysis including lymphocyte surface markers in BALF in 17 patients with DPB (14 male; 36 female) was performed. The total number of cells increased remarkably, especially the percentage of neutrophils (72.9 +/- 14.1%). On the contrary the percentage of alveolar macrophage decreased (15.4 +/- 8.9%). The CD4/CD8 ratio in DPB was also significantly decreased to 0.73 +/- 0.38% when compared with normal healthy nonsmokers. Five patients with low dose and long term EM treatment were analyzed. Total cell counts as well as the neutrophil percentage (7.3 +/- 4.0%) decreased significantly. On the other hand the percentage of alveolar macrophage increased to 76.6 +/- 0.6%, which was almost similar to those obtained from normal healthy volunteers. Therefore it is concluded that both clinical and BALF findings improved concordantly after EM treatment.

Adult↗

PubMed1991

[A case of bronchiolitis obliterans organizing pneumonia, which recurred during prednisolone maintenance therapy].

A 69-year-old man was admitted with general fatigue, dyspnea, cough, fever and right pulmonary infiltrations on a chest X-ray films. He had suffered from myocardial infarction 8 years before. Since September 1987, he had been given Aprindine in addition to previous drugs. In early November 1987, he developed dyspnea. Antibiotics were not effective. He was hospitalized on Nov. 13, '87 when crepitations were audible on his right chest. Methylprednisolone pulse therapy was effective, however right pneumothorax developed. He underwent right thoracotomy and lung biopsy. Lung biopsy specimens showed pathological features of bronchiolitis obliterans organizing pneumonia (BOOP). Corticosteroid therapy yielded a remarkable clinical, physiological and roentgenographic recovery. However, approximately two years later during prednisolone maintenance therapy, BOOP recurred. He responded again to corticosteroid treatment, however he died of hepatic failure on Dec. 17, '89. "Idiopathic" rather than "drug induced" was suggested for the cause of BOOP in this case.

Aged↗

PubMed1991

[Two cases of interstitial pneumonitis with marked increase of tumor-associated carbohydrate antigens in serum].

Tumor-associated carbohydrate antigens, CA19-9 and SLEX have been used clinically as markers for malignancy. However, it is also known that these antigens are frequently elevated in the serum of patients with benign lung diseases. We have experienced two cases of interstitial pneumonitis with marked increase of carbohydrate antigens in serum, the level of which changed according to their clinical course. Case 1. A 64-year-old woman was admitted because of a cough and exertional dyspnea. Despite treatment with various antibiotics and prednisolone, she died of respiratory failure approximately two months after admission. Her CA19-9 and SLEX in serum elevated from 500 U/ml to 5506 U/ml and 167 U/ml to 1187 U/ml respectively in accordance with clinical deterioration. Autopsy revealed no malignancy. Case 2. A 57-year-old woman, who had been suffering from interstitial pneumonitis associated with rheumatoid arthritis, was admitted with a cough and fever. She responded to prednisolone therapy, however two years later she readmitted because of exacerbation and died of respiratory failure. The initial CA19-9 level in serum was 876 U/ml and dropped to 42 U/ml with prednisolone therapy. The serum antigen level again increased during the period of exacerbation, and showed 133 U/ml immediately before death. An immunohistochemical study of CA19-9 and SLEX in various tissues obtained by autopsy was performed in case 1. The distribution of these antigens in tissue was similar to that of normal individuals. The exceptions were the expression of these antigens on epithelial cells of microscopic honeycombing and on mucinous exudates in air spaces.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed1991

[A case of lung sarcoidosis which was clinically difficult to distinguish from hypersensitivity pneumonitis].

A case of pulmonary sarcoidosis (stage III), in which the abnormal chest shadow disappeared within two weeks was reported. A 35-year-old male was admitted for further examination of bronchial asthma. He stayed overnight at home after he received inhalation provocation test of sulpyrin. Returning to the hospital, he had a fever (38 degrees C) with diffuse small nodular shadows on the chest roentgenogram. The onset and clinical features of the disease suggested hypersensitivity or drug induced pneumonitis rather than sarcoidosis. Bronchoalveolar lavage fluid (BALF) analysis showed an increase of total cell counts and lymphocytes. The surface marker of lymphocytes in BALF revealed that the CD4/8 ratio was remarkably elevated to 6.2. Both transbronchial lung and scalene node biopsy specimens revealed numerous non-caseous granulomas, and a diagnosis of sarcoidosis was confirmed. The chest infiltrates disappeared spontaneously within two weeks. This case was reported because of its rare natural course as stage III pulmonary sarcoidosis.

Adult↗

PubMed1991

[Analysis of cellular and biochemical contents of broncho-alveolar lavage fluid from patients with pulmonary tuberculosis].

To evaluate the local immune response in lung and activity of pulmonary tuberculosis. Broncho-alveolar lavage (BAL) was performed on 15 patients with pulmonary tuberculosis. Patients consisted of nine in the active stage and six in the inactive stage. Acid-fast bacilli (AFB) in BAL fluid (BALF) were found in six out of nine active stage patients (BAL-AFB positive group). The results obtained were as follows; 1) The number of total cells in BALF increased significantly in BAL-AFB positive group. BALF from two patients of this group, who were in the very early stage, revealed that the lymphocytes increased predominantly whereas neutrophils were dominant in BALF from the other four patients. 2) No case showed increase of B cells in BALF. Lymphocytes surface markers were compared between BAL-AFB positive and negative groups. No difference was found in the numbers of OKT3, OKT4 and OKT8. The positive rates of OKIal, and OKT4/8 ratio were both increased in BALF compared to the BAL-AFB positive group. 3) The numbers of OKT4 and OKT4/8 ratio in peripheral blood, which were taken simultaneously with BAL, were decreased in patients in the active stage. 4) Protein, albumin, IgG, IgA, lysozyme and alpha 1-antitrypsin levels in BALF were all increased in tuberculous patients. No correlation between the activity of tuberculosis and levels of protein, albumin, IgG and IgA was observed. Lysozyme level increased in the inactive stage of patients. On the other hand alpha 1-antitrypsin level increased in the active stage. Fibronectin level in BALF from patients was lower than that from normal controls. 5) Smoking habit had no influence on the above results. 6) Only one case showed the appearance of new lesions after BAL procedure as a complication.

Adult↗

PubMed1990

[Studies on defence effects of recombinant human granulocyte colony-stimulating factor (G-CSF) to infections. I. Induction of neutrophil polarization by G-CSF].

It is well known that recombinant human granulocyte increases dramatically the number of granulocytes in peripheral blood. It is interesting to see if G-CSF enhances the functions of neutrophil since the neutrophil is one of the most important factors of host defence mechanism against infections. In this study, we have demonstrated that G-CSF induced the polarization of neutrophil while it could not be chemoattractant for the cell. Polarization is considered to be the initial reaction of chemotaxis. Therefore, G-CSF might enhance the defence effect of the neutrophils+ to infections in this point.

Cells, Cultured↗

PubMed1990

[Studies on defense effects of recombinant human granulocyte colony-stimulating factor (G-CSF) to infections. II. Priming effect for superoxide production by human neutrophil].

In present study, we have investigated superoxide (O2-) production from human neutrophils by recombinant human granulocyte colony-stimulating factor (G-CSF) using the microtiter plate for the purpose of being close to the inflammatory site. G-CSF by itself did not induce the release of O2- in human neutrophil on either Fetal Bovine Serum (FBS)-coated plate or plate uncoated with FBS, even if neutrophils were exposed for maximum 3 hr. However, the optimal concentration of G-CSF (50 ng/ml) was able to prime human neutrophils with enhance of O2- release stimulated by the chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine (FMLP) from 10(-6) to 10(-8) M, but not by the non chemoattractant such as phorbol myristate acetate (PMA), concanavalin A, and ionomycin. These findings indicate that G-CSF might enhance bactericidal activity of neutrophils by priming them penetrating into the inflammatory site.

Cells, Cultured↗

PubMed1990

[Studies on defence effects of recombinant human granulocyte colony-stimulating factor (G-CSF) to infections. III. Protective effect on pulmonary and systemic infections of P. aeruginosa in neutropenic mice].

In the prior two reports, we demonstrated that G-CSF induced the polarization of neutrophils by itself, and also enhanced superoxide production from neutrophils stimulated by the chemotactic peptides. In this study, we have examined the protective effect of G-CSF in vivo on Pseudomonas pneumonia and septicemia in mice. Cyclophosphamide (CY) induced severe reduction of the number of peripheral leukocytes and weakened resistance for Psuedomonas aeruguinosa infection of mice. However, in mice receiving recombinant human G-CSF four daily subcutaneous injection, the number of leukocytes, particulary neutrophils, increased more rapidly than in controls receiving saline. Moreover G-CSF enhanced a protective effect to pulmonary and systemic pseudomonas infections. When G-CSF was administered together with antibiotics, significant synergism in the protection against pulmonary infection of Pseudomonas was observed. Carrageenan treatment decreased the protective effect of G-CSF. These results suggested that the protective effect of G-CSF against P. aeruginosa infection depends not only on PMN but also another complexed host defence mechanism.

Animals↗

PubMed1990

Detection of three sialylated tumor-associated antigens in malignant serous effusions.

One hundred thirty-seven fluid samples from patients with malignant diseases, including 58 with lung cancer and 36 with gastric carcinoma, were screened for three tumor-associated carbohydrate antigens. The antigens tested were sialylated Lewis (SLEX) antigen, sialylated SSEA-1 (SLX) antigen, and sialylated Lewis (CA19-9) antigen. Thirty-four fluid samples from patients with benign diseases including 20 with tuberculous pleurisy were also tested for these three antigens as a control. SLEX antigen had the highest positivity rate among the three antigens both in the pleural effusions of patients with pulmonary adenocarcinoma and for all types of lung cancer (64.1% and 46.6%, respectively). In cancers of digestive system, the percentage of SLEX positivity was almost same as that for CA19-9, and higher than that for SLX. A combination assay using the three antigens resulted in an increased rate of detection of tumor-associated antigens (68% of 58 lung cancers including 83% of 39 adenocarcinomas, as well as 77% of 63 digestive system cancers including 84% of 36 gastric carcinomas). Gel filtration of pleural effusions or bile using sephacryl S-1000 showed that these three antigens were eluted in the void volume, indicating a molecular weight of greater than 2 X 10(6). Thus, all 3 antigens possibly exist on carrier protein with a high molecular weight. These observations suggest the potential application of these antigens to distinguish between benign and malignant fluid, and to monitor the effects of the treatment of various types of cancer.

Antigens, Tumor-Associated, Carbohydrate↗

PubMed1990

[Two cases of bronchiolitis obliterans organizing pneumonia, showing multiple infiltrative shadows, diagnosed by open lung biopsy, and a report of their BAL findings].

Two cases of bronchiolitis obliterans organizing pneumonia (BOOP) were diagnosed by clinical features and pathological findings of open lung biopsy specimens. Findings of repeated (bronchoalveolar lavage (BAL) fluid analysis were also reported. Case 1 was a 54 year-old woman complaining of dry cough and low grade fever. Multiple infiltrative shadows in both lung fields were pointed out on her chest roentgenogram. Case 2 was a 68 year-old woman with symptoms of cough, sputum and low grade fever. Her chest X-ray films also showed multiple infiltrative shadows bilaterally. Although various antibiotics were given to both patients, new shadows appeared on their chest films without any improvement of clinical symptoms or inflammatory findings. TBLB specimens obtained from the two cases showed the findings of organizing pneumonia. In each case, open lung biopsy was performed, and the pathological diagnosis was consistent with BOOP. However, exclusion of the possibility of eosinophilic pneumonia and lymphoproliferative disorders of the lung was somewhat difficult in case 1. BALF analysis showed an increased number of lymphocytes in both cases, 75% and 37% respectively. The inverted ratio of OKT4/OKT8 (0.71) in BALF of case 1 was similar to that of hypersensitivity pneumonitis. In spite of clinical and roentgenological improvement after steroid therapy, the abnormal BAL findings still remained. Therefore it is suggested that BAL may be a useful tool for monitoring the steroid treatment of patients with BOOP.

Aged↗

PubMed1990

[A case of idiopathic pulmonary fibrosis with chronic eosinophilic pneumonia].

A 58 year-old man was admitted to our hospital with complaints of dyspnea and cough. Chest X-ray examination revealed diffuse nodular shadow, infiltration in the left upper and lower lobes, and volume loss. BALF showed increased number of cells, particularly eosinophils (65.6%). Eosinophilia (17-13%) was also seen. The histological examination of the TBLB specimen revealed irregular thickening and edema of alveolar septa. From these findings together with clinical features the case was diagnosed as eosinophilic pneumonia. Oral administration of prednisolone started with 30 mg. Within a week, eosinophilia in peripheral blood decreased to 1%, PaO2 increased to 87.5 Torr in room air, and CRP became negative. His chest X-ray film showed the disappearance of infiltrative shadows in the left upper and lower lobes. On the 19th day was prednisolone decreased to 20 mg. Laboratory data and chest roentgenogram showed exacerbation, and PaO2 gradually decreased to 62.9 Torr. Patchy shadows were seen in the right upper lobe. The dose of prednisolone was again increased to 60 mg/day, and was quite effective. The drug dosage was tapered by 10 mg/10 days to 40 mg/day, however all data exacerbated again. The clinical course seemed peculiar for eosinophilic pneumonia, however small reticulonodular shadows on chest X-ray did not change. Therefore, open lung biopsy was performed. The histology of the specimen showed fibrosis, lymphocyte infiltration and thickening of alveolar septa. The clinical course and histopathological findings led to a diagnosis of idiopathic pulmonary fibrosis accompanied with chronic eosinophilic pneumonia.

Biopsy↗

PubMed1990

[Three cases of pulmonary atypical mycobacteriosis associated with lung cancer and adult T-cell leukemia].

Three cases of pulmonary atypical mycobacteriosis (AM) were reported. Two cases were associated with lung cancer in which the diagnosis of malignancy was difficult and delayed by the coexistence of AM. The third was a case of adult T-cell leukemia (ATL) which manifested during the course of AM. In case 1 (73 years, male) and case 2 (86 years, male), chest roentgenogram abnormalities as well as clinical symptoms were considered to be caused by mycobacteriosis because of positive smear of acid-fast bacilli in sputa on admission. Therefore it took four months and three months respectively for final diagnosis of lung cancer. The autopsy of case 1 revealed a poorly differentiated adenocarcinoma with coexisting foci of squamous cell carcinoma in right lower lung, and granulomatous inflammations with caseating necroses in right mid and lower lungs. M. avium complex was cultured from sputum on admission, and also a high titer of HTLV-I antibody was demonstrated. In case 2 malignant cells were detected in sputa (class V), however his general condition did not allow an aggressive anticancer chemotherapy and he died of malignancy with complication of thromboangiitis obliterans on right lower leg. Case 3 was a 76-year-old male who had been diagnosed as lung AM for more than two years. His chest radiography showed bilateral infiltrative shadows with frequent positive cultures of M. avium complex (more than 100 colonies) from sputum. A generalized lymphadenopathy including right hilar lymph node on chest X-ray film was followed by the presence of atypical lymphocytes in peripheral blood and the elevation of HTLV-I antibody in serum. Four months later he died with hypercalcemia and renal failure in spite of chemotherapy (CPM + VCR + ADR + PLS). The above cases suggest that AM as well as tuberculosis should be considered when pulmonary infiltrates were observed in malignant patients, especially in patients with retrovirus infections.

Aged↗